1. Field of the Invention
The present invention relates to drug delivery systems and, more specifically, to polysialic acid and polycaprolactone micelles for the delivery of hydrophobic drugs.
2. Description of the Related Art
Due to the high cost and lengthy implementation timeline involved with drug discovery, drug delivery may serve as an alternative method to advance pharmaceutical sciences and human health. In addition, a numbers of therapeutics are characterized by poor bioavailability, unfavorable biodistribution, and high cytotoxicity, particularly when administered systemically. Drug carrier systems are needed to improve drug efficacy and reduce cytotoxicity in the human body. To date, many studies have been conducted based on the theory proposed by Paul Ehrlich to develop therapeutics which can be site-specifically delivered to the target tissue, with reduced accumulation in the healthy tissue. Most of these delivery systems are designed with the advantages of increased drug solubility, prolonged circulatory stability, and high tissue specificity.
Among various nanoparticle systems, polymeric micelles have drawn much attention for the encapsulation of hydrophobic. These micelles are formed from macromolecules composed of hydrophobic and hydrophilic segments. In an aqueous environment, the amphiphilic polymers self-assemble into a core-shell structure due to the aggregation of the hydrophobic moieties. Thus, hydrophobic drugs can be physically encapsulated into the core via hydrophobic interactions. In general, micelles provide therapeutics with improved solubility, enhanced stability, and an extended circulation time.
When administered systemically, drug delivery systems without sufficient hydrophilicity to reduce the recognition and binding of plasma proteins are often eliminated rapidly by the reticuloendothelial system (RES). Thus, by increasing the surface hydrophilicity, the rate of elimination can be decreased and the circulation time can be prolonged, thereby improving the likelihood that the drugs will reach the target disease tissues. To date, poly(ethylene glycol) (PEG)-based modification has been the most common method to improve hydrophilicity and provide the drugs with so-called “stealth” properties to evade detection by the RES. However, PEG may not be the ideal solution due to a non-biodegradable backbone, evidence of continuous accumulation inside the body, and problems with immunogenicity. Moreover, the PEG coating is known to interfere with some of the steps involved in drug delivery. After localization to the diseased tissue, PEG coatings have been reported to hinder drug release from the carrier systems and reduce requisite drug-cell interactions.
As an alternative, polysialic acid (PSA) is a relatively unexplored natural, non-toxic, and biodegradable polysaccharide that has the potential to prolong the circulation time of associated drugs and provide additional benefits. PSA is a linear homopolymer of α-2, 8-linked 5-Nglycolyneuraminic acid (Neu5Ac) and is widely produced by pathogenic bacteria, as well as the cells of vertebrates and higher invertebrates. Thus, PSA is highly involved and has multifarious roles in a wide variety of biological, immunological, and pathological processes. Some pathogenic bacteria can escape the host immune system and evade the host tissues by producing a thick PSA coating on the cell wall. In mammals, the major function of PSA is believed to be the anti-adhesive properties that can change the cell-cell and cellextracellular matrix interaction and promote neural plasticity. PSA acts as a post-translational modification of neural cell adhesion molecules (NCAM), and the fifth Ig domain of NCAM is able to carry PSA at a high loading capacity. The significant negative charge and large hydrated volume of PSA can reduce NCAM-mediated adhesion and enable neuron cell migration. Typically, PSA expression is down-regulated in most tissues of the adults. However, during the neural injuries and tumorigenesis, PSA is expressed on the cell surfaces, which serves to alter cellular interactions to abrogate cell adhesion and facilitate cell migration. The anti-adhesive properties are further supported by immune studies that demonstrate that the removal of PSA generates an “eat me” signal to macrophages to recognize and clear the uncoated bacteria, excess proteins, or dead cells.
Due to the natural anti-adhesive properties highlighted above, PSA has drawn attention in the field of drug delivery. Based on a series of studies on sialylated or polysialylated proteins, it has been proposed that PSA was a potential material to increase the stability and circulation time of therapeutics inside the bodies. PSA-drug conjugation has been used to increase the half-life of insulin, asparaginase, and catalase. As a result, immunogenicity and antigenicity were reduced, and the efficacy of the proteins was improved. To date, several PSA-protein conjugates and Neu5Ac derivatives have been developed as vaccines and therapeutic agents.
Compared to other drug delivery systems, nanoparticle-based targeted drug delivery systems have been shown to accumulate passively within tumor tissue and inflamed tissue due to the enhanced permeability of the leaky vasculature. Micelles from PSA modified with a long chain hydrocarbon, decylamine have been developed. Despite possessing the necessary physical properties in regards to size and surface charge, these micelles were cytotoxic towards a synovial fibroblast cell line.